Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses

Sun Hee Ahn, Hitesh Deshmukh, Nicole Johnson, Lindsay G. Cowell, Thomas H. Rude, William K. Scott, Charlotte L. Nelson, Aimee K. Zaas, Douglas A. Marchuk, Sehoon Keum, Supaporn Lamlertthon, Batu K. Sharma-Kuinkel, Gregory D. Sempowski, Vance G. Fowler

Research output: Contribution to journalArticle

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Abstract

Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N2 backcross mice (F1 [C18A]×C57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus-challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 β and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies.

Original languageEnglish (US)
Article numbere01088
JournalPLoS Pathogens
Volume6
Issue number9
DOIs
StatePublished - Sep 2010

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Chromosomes, Human, Pair 18
Quantitative Trait Loci
Staphylococcus aureus
Infection
Genes
Chromosomes
Sepsis
Cytokines
Chromosomes, Human, Pair 8
Chromosomes, Human, Pair 11
Medical Genetics
Peritoneal Macrophages
Genetic Predisposition to Disease
Granulocyte-Macrophage Colony-Stimulating Factor
Interleukin-1
Inbred C57BL Mouse
Small Interfering RNA
Real-Time Polymerase Chain Reaction
Macrophages
Genome

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses. / Ahn, Sun Hee; Deshmukh, Hitesh; Johnson, Nicole; Cowell, Lindsay G.; Rude, Thomas H.; Scott, William K.; Nelson, Charlotte L.; Zaas, Aimee K.; Marchuk, Douglas A.; Keum, Sehoon; Lamlertthon, Supaporn; Sharma-Kuinkel, Batu K.; Sempowski, Gregory D.; Fowler, Vance G.

In: PLoS Pathogens, Vol. 6, No. 9, e01088, 09.2010.

Research output: Contribution to journalArticle

Ahn, SH, Deshmukh, H, Johnson, N, Cowell, LG, Rude, TH, Scott, WK, Nelson, CL, Zaas, AK, Marchuk, DA, Keum, S, Lamlertthon, S, Sharma-Kuinkel, BK, Sempowski, GD & Fowler, VG 2010, 'Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses', PLoS Pathogens, vol. 6, no. 9, e01088. https://doi.org/10.1371/journal.ppat.1001088
Ahn, Sun Hee ; Deshmukh, Hitesh ; Johnson, Nicole ; Cowell, Lindsay G. ; Rude, Thomas H. ; Scott, William K. ; Nelson, Charlotte L. ; Zaas, Aimee K. ; Marchuk, Douglas A. ; Keum, Sehoon ; Lamlertthon, Supaporn ; Sharma-Kuinkel, Batu K. ; Sempowski, Gregory D. ; Fowler, Vance G. / Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses. In: PLoS Pathogens. 2010 ; Vol. 6, No. 9.
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abstract = "Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N2 backcross mice (F1 [C18A]×C57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus-challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 β and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies.",
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AU - Deshmukh, Hitesh

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AU - Cowell, Lindsay G.

AU - Rude, Thomas H.

AU - Scott, William K.

AU - Nelson, Charlotte L.

AU - Zaas, Aimee K.

AU - Marchuk, Douglas A.

AU - Keum, Sehoon

AU - Lamlertthon, Supaporn

AU - Sharma-Kuinkel, Batu K.

AU - Sempowski, Gregory D.

AU - Fowler, Vance G.

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N2 - Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N2 backcross mice (F1 [C18A]×C57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus-challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 β and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies.

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